World J Urol DOI 10.1007/s00345-013-1230-0
ORIGINAL ARTICLE
Impact of positive surgical margins and their locations after radical prostatectomy: comparison of biochemical recurrence according to risk stratification and surgical modality Min Soo Choo • Sung Yong Cho • Kyungtae Ko • Chang Wook Jeong Seung Bae Lee • Ja Hyeon Ku • Sung Kyu Hong • Seok-Soo Byun • Cheol Kwak • Hyeon Hoe Kim • Sang Eun Lee • Hyeon Jeong
•
Received: 8 September 2013 / Accepted: 12 December 2013 Ó Springer-Verlag Berlin Heidelberg 2013
Abstract Purpose We investigated the influence of positive surgical margins (PSMs) and their locations on biochemical recurrence (BCR) according to risk stratification and surgical modality. Methods A total of 1,874 post-radical-prostatectomy (RP) patients of pT2–T3a between 2000 and 2010 at three tertiary centers, and who did not receive neoadjuvant/adjuvant therapy, were included in this study. Patients were stratified according to BCR risk: low risk (PSA \10, pT2a-b, and pGS B6), intermediate risk (PSA 10–20 and/or pT2c and/or pGS 7), and high risk (PSA[20 or pT3a or pGS 8–10). The median follow-up was 43 months. Results PSMs were a significant predictor of BCR in both the intermediate- and high-risk-disease groups (P = .001, HR 2.1, 95 % CI 1.3–3.4; P \ .001, HR 2.8, 95 % CI 2.0–4.1). Positive apical margin was a significant risk factor for BCR in high-risk disease (P = .003, HR 2.0, 95 % CI 1.2–3.3), but not in intermediate-risk disease
(P = .06, HR 1.7, 95 % CI 0.9–3.1). Positive bladder neck margin was a significant risk factor for BCR in both intermediate- and high-risk disease (P \ .001, HR 5.4, 95 % CI 2.1–13.8; P = .001, HR 4.5, 95 % CI 1.8–11.4). In subgroup analyses, robotic RP provided comparable BCR-free survival regardless of risk stratification. Patients with PSMs showed similar BCR-free survival between open and robotic RP (log-rank, P = .897). Conclusions Post-RP PSMs were a significantly independent predictor of disease progression in high-risk disease as well as intermediate-risk disease. Both positive apical and bladder neck margins are also significant risk factors of BCR in high-risk disease. Patients with PSMs showed similar BCR-free survival between open and robotic surgery. Keywords Prostatic neoplasms Prostatectomy Neoplasm Residual Disease-free survival Robotics
Introduction M. S. Choo C. W. Jeong J. H. Ku C. Kwak H. H. Kim Department of Urology, Seoul National University Hospital, 28, Yongon-dong, Chongno-gu, Seoul 110-744, Korea S. Y. Cho S. B. Lee H. Jeong (&) Department of Urology, Seoul National University Boramae Hospital, Sindaebang 2-dong, 395, Dongjak-gu, Seoul 156-707, Korea e-mail: [email protected]; [email protected] K. Ko Department of Urology, Kangdong Sacred Heart Hospital, 150, Seongan-ro, Gangding-gu, Seoul 134-701, Korea S. K. Hong S.-S. Byun S. E. Lee Department of Urology, Seoul National University Bundang Hospital, 300 Gumi-dong, Bundang-gu, Seongnam-si, Seongnam 463-707, Korea
Positive surgical margin (PSM) implies incomplete tumor resection in surgical beds [1]. Its oncological significance to disease progression, however, remains controversial [2]. One recent study reported that PSM is not a significant risk factor for biochemical recurrence (BCR) in low- and highrisk diseases [3]. Also, controversial is the impact of PSM locations on BCR. The literature contains many conflicting reports. With respect specifically to the effect of positive apical margin (?AM) on BCR, the literature offers many contradictory reports [4]. The positive basal margin (?BM) is generally known to be a risk factor [5], though one investigator showed that it is not an independent predictor of BCR in low Gleason grade disease [6].
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Some reports have indicated that PSM rates might be related to surgical modalities and technique [7–9]. Another study recently showed that in high-stage disease, higher PSM rates are associated more with robot-assisted laparoscopic radical prostatectomy (RALP) rather than with retropubic radical prostatectomy (RRP), but that in low-stage disease, PSM rates do not differ [10]. However, there has been no study comparing the two modalities for BCR according to risk stratification. Moreover, there is no known comparative RRP/RALP study on how PSMs effect BCR. In the present study, we investigated the influence of PSMs and their locations on disease progression with pathological stage T2–T3a patients according to risk stratification and surgical modality.
Methods A total of 3,465 consecutive patients who had undergone RRP or RALP for clinically localized prostate cancer between January 2000 and December 2010 at three tertiary referral centers representing the same institution were enrolled in this study. Upon the approval of our institutional review board, we retrospectively collected clinical and pathological information on those patients. Follow-up data were gathered by means of chart review. All surgeons, who participated in this study, were experts and experienced enough to open (87–564 cases) or laparoscopic (over 150 cases) prostatectomy, and several reports showed that an experienced open surgeon successfully transferred open surgical skills to a robotic surgery in 8–25 cases [11, 12]. Therefore, with respect to each surgeon, the first 25 patients to undergo RALP were excluded owing to the learning curve. Additionally, a total of 252 patients who had undergone neoadjuvant therapy were excluded from the study. In order to isolate the effect of PSM locations on BCR, 469 patients with seminal vesicle invasion and/or positive lymph nodes, along with 254 patients who had undergone adjuvant therapy, were excluded. Also, 377 patients with\6 months of the followup and 24 patients with missing data were excluded. The patients with a detectable range of PSA over 0.2 ng/ml at the first follow-up visit were treated with adjuvant hormone therapy or radiotherapy, so those patients were excluded from the analyses. Thus, our final subjects numbered 1,874 patients were with disease of T2 and T3a pathological stages. The procedure according to which pathological specimens were processed was identical at each of the three hospitals. Prostatectomy specimens were processed according to the whole-mount technique and following the Stanford procedure, and were evaluated by 4 expert uro-
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pathologists. PSMs, defined as cancer cells reaching the inked surface, were categorized into four groups according to location: apex, bladder neck, posterolateral, and multifocal. Pathological staging was done using the seventh edition AJCC cancer staging system [13]. Follow-up visits were scheduled at 3-month intervals for 1 year, then semiannually for 1 year, and annually thereafter. Serum PSA level was checked at each follow-up visit. BCR was defined as a PSA [0.2 ng/ml or more on two consecutive measurements. Patients were stratified by BCR risk according to the modified D’Amico criteria as follows: low risk (PSA \10, pT2a–b stage, and GS B6), intermediate risk (PSA 10–20 and/or pT2c stage and/or GS 7), and high risk (PSA[20 or pT3a stage or GS 8–10) [14]. Robotic surgery at our institution begun in July 2008. In a subgroup analysis comparing robotic with open surgery, patients who had undergone RRP since that time were included. The choice of surgical approach accorded with patient preference after discussion of the risks, benefits, and alternatives with the attending surgeon. RRP was performed using the modified Walsh anatomical modality, and RALP was performed, using the transperitoneal antegrade approach and the da Vinci Robot System. We performed pelvic lymph node dissection (PLND) in most of the high-risk patients in D’Amico criteria, and the necessity of PLND in intermediate-risk patients was determined with the discretion of attending surgeon. The boundary of PLND included obturator, and external and internal iliac lymph nodes in most patients. The nerve-sparing procedure was performed if clinically indicated by patient age, preoperative erectile function, and oncological parameters. Comparisons between subject groups were conducted using the Student’s t test or Pearson v2 test, and the respective clinicopathological variables were analyzed using Pearson v2 tests. To determine the effect of risk group as well as surgical margin status and its location on BCR risk, Kaplan–Meier curves were generated, and differences were compared by log-rank test and Cox proportional hazard regression analysis. Significant variables on univariate analysis were included in the multivariate model. A two-sided P value \.05 was considered significant. Statistical results were calculated using the SPSS software package (ver. 14.0, SPSS Inc., Chicago, IL, USA).
Results The clinical and pathological characteristics of the 1,874 patients are provided in Table 1. Overall, 462 (24.7 %) patients were reported to have PSMs. The PSM rate rose from 8.9 % in low-, to 20.3 % in intermediate-, and to 32.6 % in high-risk disease (P \ .001). With a median follow-up of 43 months, 245 (13.1 %) patients experienced
World J Urol Table 1 Clinicopathological characteristics according to SMs status and their locations (%) Characteristics
Overall
SMs status Negative
P value Positive
Apex
N
1,874
1,411 (75.3)
463 (24.7)
Age (years)
65.3 ± 6.9
65.1 ± 7.0
65.9 ± 6.5
PSA (ml/ng)
8.5 ± 6.9
8.0 ± 6.2
9.8 ± 8.6
\10
1,410 (75.2)
1,091 (77.3)
317 (68.5)
10–20
365 (19.5)
258 (18.2)
108 (23.3)
[20
99 (5.3)
62 (4.4)
38 (8.2)
Biopsy GS 6 or less
SMs locations
P value BN
190 (10.1)
32 (1.7)
65.6 ± 6.2
66.5 ± 5.8
.458
\.001
9.5 ± 8.3
7.7 ± 5.0
.264
\.001
140 (73.7)
23 (71.9)
.459
35 (18.4)
8 (25.0)
15 (7.8)
1 (3.1)
105 (55.3)
18 (56.2)
.027
\.001
.790
1,145 (61.1)
897 (63.5)
248 (53.5)
7
528 (28.2)
381 (27.0)
147 (31.7)
56 (29.4)
10 (31.2)
8–10
201 (10.7)
133 (9.4)
68 (14.6)
29 (15.3)
4 (12.5)
T1
1,346 (71.8)
1,031 (73.0)
315 (68.0)
130 (68.4)
24 (75.0)
T2
528 (28.2)
380 (26.9)
148 (31.9)
60 (31.6)
8 (25.0)
191 (10.2)
174 (12.4)
17 (3.7)
7 (3.7)
2 (6.3)
Intermediate
819 (43.7)
652 (46.2)
165 (35.7)
85 (44.7)
14 (43.8)
High
864 (46.1)
585 (41.4)
281 (60.6)
98 (51.5)
16 (50.0)
Prostate (vol, ml)
40.9 ± 17.6
42.0 ± 18.0
37.4 ± 15.8
37.1 ± 4.6
35.9 ± 7.9
Clinical stage
.045
\.001
Risk group Low
.457
Op. methods
\.001
.803
.450
.537 .265
RRP
1,277 (68.1)
968 (68.6)
309 (66.7)
147 (77.4)
RALP
597 (31.9)
443 (31.4)
154 (33.3)
43 (22.6)
21 (65.6) 11 (34.3)
PLND NVB saving
622 (33.2) 769 (41.0)
447 (31.6) 577 (40.8)
175 (37.7) 192 (41.4)
.008 .596
54 (28.7) 72 (38.3)
11 (34.3) 13 (40.7)
.277 .673
Tumor (vol, ml)
4.2 ± 13.5
3.7 ± 15.2
5.5 ± 6.4
.020
5.1 ± 4.6
5.5 ± 4.6
.661
pT2a, b
443 (23.6)
389 (27.5)
54 (11.6)
25 (13.2)
5 (15.6)
pT2c
661 (35.2)
509 (36.1)
152 (32.8)
79 (41.5)
13 (40.6)
pT3a
770 (41.1)
513 (36.4)
257 (55.5)
86 (45.3)
14 (43.8)
\.001
Pathological stage
.731
\.001
Pathological GS
.476
6 or less
734 (39.1)
609 (43.2)
125 (27.0)
46 (24.2)
7
1,047 (55.8)
738 (52.3)
309 (66.7)
130 (68.4)
19 (59.4)
8–10
93 (5.0)
64 (4.5)
29 (6.3)
14 (7.4)
2 (6.2)
BCR. The BCR rates were 6.8 % in low-, 11.6 % in intermediate-, and 15.9 % in high-risk disease. Figure 1 shows the effect of surgical margin status on BCR risk according to the disease group. Among all of the patients, PSM was an independent predictor of BCR. Pelvic lymph node dissection or neurovascular bundle sparing was not associated with BCR. Patients with low-risk disease had similar risks of BCR regardless of surgical margin status and locations. By contrast, in patients with both intermediate- and high-risk disease, PSM was a significant predictor of BCR on univariate analysis (P = .001 and P \ .001). On multivariate analysis, including preoperative PSA level, pathological stage, and Gleason score, PSM was an independent predictive factor of BCR in patients with
11 (34.4)
both intermediate- and high-risk disease (HR 2.1 and 2.8) (Table 2). Figure 1 also shows the impact of PSM location on BCR according to risk group. Both ?AM and ?BM were significant risk factors for BCR among all of the patients. On univariate analyses, ?AM and ?BM were significant predictors of BCR in both the intermediate- and high-riskdisease groups. However, on multivariate analyses, the impact of ?AM did not attain significance in the intermediate-risk group (P = .06, HR 1.7, 95 % CI 0.9–3.1). In the high-risk group, by contrast, ?AM was a significant risk factor for BCR (HR 2.0). ?BM was a significant independent predictor of BCR in both the intermediate- and high-risk groups (HR 5.4 and HR 4.5) (Table 2).
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Fig. 1 BCR-free survival stratified by margin status and its sites according to risk-disease groups. a Overall. b Low risk. c Intermediate risk. d High risk
In a subgroup analysis comparing the surgical modalities, 352 and 559 patients received RRP or RALP since July 2008, respectively. The median follow-up was 35 months in the RRP group and 39 months in the RALP group. Patients undergoing RALP had a significantly lower age and prostate volume, but similar PSA, pathological stage, and pathological Gleason scores. There was no significant difference in the PSM rates between the RRP and RALP groups (23.7 vs. 25.2 %). On survival analysis, the overall BCR-free survival rates were similar in the two treatment groups (Fig. 2a). Neither were there significant
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differences for risk group stratification (Fig. 2). On multivariate analysis, the surgical modality was not a significant predictor of BCR (P = .718, HR 0.9, 95 % CI 0.5–1.5) (Table 2). The impact of PSMs on BCR was similar in the RRP and RALP groups (Fig. 3).
Discussion The present results indicate that PSMs in RP specimens without seminal vesicle or lymph node involvement are
World J Urol Table 2 Multiple Cox proportional hazards models for BCR predictors Risk group
Variables
Overall
SM
PSA GS pStage
Low
Intermediate
High
Stratification
P
HR
95 % CIs
-SM versus ?SM
\.001
2.6
1.9–3.4
-SM versus ?AM
\.001
1.9
1.3–2.7
-SM versus ?BM
\.001
5.0
2.7–9.4
\10 versus 10–20
\.001
1.7
1.2–2.3
\10 versus C20
\.001
2.2
1.4–3.5
6 versus 7
.002
1.7
1.2–2.4
6 versus 8, 9, 10
\.001
4.5
2.8–7.2
2a, b versus 2c
.20
1.2
0.8–1.8
2a, b versus 3a
.54
1.1
0.7–1.6
Op.
RRP versus RALP
.718
0.9
0.5–1.5
SM PSA
-SM versus ?SM -
.07 –
3.2 –
0.8–11.9 –
GS
-
–
–
–
pStage
-
–
–
–
SM
-SM versus ?SM
.001
2.1
1.3–3.4
-SM versus ?AM
.06
1.7
0.9–3.1
-SM versus ?BM
\.001
5.4
2.1–13.8
PSA
\10 versus 10–20
.04
1.5
1.0–2.4
GS
6 versus 7
.08
1.5
0.9–2.5
pStage
2a, b versus 2c
.02
2.1
1.3–3.3
SM
-SM versus ?SM
\.001
2.8
2.0–4.1
-SM versus ?AM
.003
2.0
1.2–3.3
-SM versus ?BM
.001
4.5
1.8–11.4
\10 versus 10–20
.007
1.7
1.1–2.7
\10 versus C20
.001
2.2
1.4–3.6
PSA GS pStage
6 versus 7
.001
3.1
1.5–6.3
6 versus 8, 9, 10
\0.001
8.1
3.7–17.6
2a, b versus 2c
.95
0.9
0.4–2.2
2a, b versus 3a
.94
0.9
0.4–2.0
Low-risk group: PSA \ 10 and GS B 6 and pStage 2a or 2b, intermediate-risk group: PSA 10–20 or GS 7 or pStage 2c, high-risk group PSA C 20 or GS C 8 or pStage 3a
significant predictive factors for disease progression in both intermediate- and high-risk disease. Furthermore, both ?AM and ?BM are significant independent predictors of BCR in high-risk disease. Subgroup analyses showed similar BCR-free survival for RRP and RALP regardless of risk stratification. Patients with PSMs, moreover, showed similar BCR-free survival rates between RRP and RALP. To our knowledge, this is the first study comparing BCR rates among a contemporary series of Asian patients undergoing either RRP or RALP. In this study, PSM patients in intermediate- and highrisk-disease groups had higher rates of BCR than those who were margin-negative. However, PSM in the low-riskdisease group was not associated with disease progression. Corcoran et al. [3] insisted that in low- or high-risk disease, PSMs are not associated with BCR, because they are only a reflection either of indolent low-risk nature or inherent
aggressiveness. However, in our data on Korean men, PSMs also were an independent predictor of BCR in the high-risk-disease group. Additionally PSMs had a more adverse effect in the high-risk-disease group than in the intermediate-risk-disease group (HR 2.8 vs. 2.1). Most recently studies reported that PSMs in high-grade and highstage disease are more relevant to recurrence risk [15, 16]. In our results, we observed that about 75 % of patients with extremely high-risk-disease features such as GS C8, PSA C20, and extracapsular extension enjoyed BCR-free survival for over 8 years after undergoing complete resection. Thus, all surgeons should attempt to achieve negative surgical margins regardless of disease status and should also actively consider adjuvant therapy for high-risk-disease patients with PSMs. After adjusting for differences in clinical and pathological features, the presence of ?BM was significantly
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Fig. 2 BCR-free survival stratified by surgical modalities according to risk-disease groups. a Overall. b Low risk. c Intermediate risk. d High risk
associated with a shorter time to recurrence in intermediate- and high-risk disease. Spahn et al. [5] suggested that patients with PSMs at the bladder neck can be considered to have the poorest prognosis (HR 4.4). Nyarangi-Dix et al. [17] also noted that ?BM is usually associated with higherstage tumor. In our data, the ?BM patients accounted for 93.8 % of the combined membership in the intermediateand high-risk-disease groups. Villers postulated that the base of the prostate wound offers a preferred pathway for cancer dissemination between intraprostatic and periprostatic neural tissue close to the superior neurovascular
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bundle [18]. Emphatically, ?BM indicates that aggressive cancer remains on the pathway to systemic dissemination. In the present study, patients with ?AM were 1.9 times more likely to have a shorter time to recurrence (P \ .001) overall. In high-risk disease, the ?AM also was associated with the time to recurrence, but not statistically in intermediate-risk disease (P = .06). Although several theories have been proposed to explain how ?AM can be less likely to result in BCR than other locations, Ohori et al. [19] reported that apical disease correlates with higher tumor volume, a higher incidence of extracapsular extension, and
World J Urol
Fig. 3 BCR-free survival stratified by surgical modalities and margin status
higher tumor grade. Pettus et al. [4] implied that ?AM is important in high-stage disease, but less important in lowstage disease. In Korean men with a relatively small prostate volume, ?AM can be a true positive rather than false one. Patel et al. [20] described that significantly greater incidence of PSMs in the smaller than in the larger prostate weight group. Actually, our data showed that patients who experienced BCR with ?AM had a smaller prostate volume than those who did not (34 vs. 37 g), but not to a statistically meaningful extent (P = .228). Thus, ?AM also should be kept in mind as a risk factor when considering further management in Korean men. We found that surgical modality was not a risk factor for disease progression. Recently, Savdie et al. [6] found that the Gleason grade of a PSM identified patients at increased risk of BCR. Similarly, we assumed that the pathological features of the remaining tumors at the PSM after surgery might be different between the two surgical modalities, because of the different surgical technique. We also investigated the influence of PSMs on the BCR according to risk stratification, because more aggressive tumors could be remained at the PSM in high-risk patients group. Thus, the similar PSM rate would not mean the similar BCR rate, and the prognostic value of PSM may be different in RALP compared to RRP. Several recent studies have reported similar BCR rates for RRP and RALP groups, but those were limited by the short follow-up or small patient groups [21–24]. In our contemporary, relative large- and mid-term studies, there was no significant difference in the BCR risk between the RALP and
RRP groups after adjustment for differences in clinical and pathological features. Although there are a few previous reports that surgical modality affects PSM rates [7, 10], the impact of PSMs on BCR likelihood was similar between the two present-study groups. To our knowledge, this is the first investigation to compare BCR between RRP and RALP according to PSMs. In the results, post-RP PSMs were associated with higher BCR rates and shorter times to progression, regardless of surgical modality. A limitation of this investigation is the relatively short follow-up periods for RALP patients. Nonetheless, considering that the most recent relevant large-scale studies reported a median post-RP time to recurrence of 24–37 months [25–28], our mean 36.3-month (median 39 months) follow-up data are perhaps reasonable. And this study is inherent in any retrospective, nonrandomized analysis. The difference in costs between the two modalities is great, so randomized controlled study cannot be performed in Korea. Nevertheless, we were careful to apply a number of strict inclusion and exclusion criteria. Thus, there was minimal bias in the subjects. Another limitation is the lack of a central pathological review. However, as the three hospitals involved in the present investigation are affiliated with the same institution, all of the participating pathologists used exactly the same pathological evaluation methods. Also, all of the specimenexamining pathologists were urology specialists. High margin rate in organ-confined disease of this cohort is one of the drawbacks of the present study. The pelvis shape of Korean men was narrow and deep, and it makes surgery difficult. The ethnic differences in the clinicopathological characteristics of prostate cancer are thought to be affected [29]. Also, our institutions are tertiary referral centers, and it might not reflect epidemiological trends.
Conclusions In conclusion, this study demonstrates that post-RP PSMs are significant independent predictors of disease progression in both high-risk and intermediate-risk disease. Both ?AM and ?BM, furthermore, also are significant BCR risk factors in high-risk disease. In the results of subgroup analyses, RALP could provide comparable BCR-free survival regardless of risk stratification. Conflict of interest
None.
References 1. Blute ML, Bostwick DG, Bergstralh EJ, Slezak JM, Martin SK, Amling CL, Zincke H (1997) Anatomic site-specific positive margins in organ-confined prostate cancer and its impact on
123
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2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
outcome after radical prostatectomy. Urology 50(5):733–739. doi:10.1016/S0090-4295(97)00450-0 Boorjian SA, Tollefson MK, Thompson RH, Rangel LJ, Bergstralh EJ, Karnes RJ (2012) Natural history of biochemical recurrence after radical prostatectomy with adjuvant radiation therapy. J Urol 188(5):1761–1766 Corcoran NM, Hovens CM, Metcalfe C, Hong MK, Pedersen J, Casey RG, Peters J, Harewood L, Goldenberg SL, Costello AJ, Gleave ME (2012) Positive surgical margins are a risk factor for significant biochemical recurrence only in intermediate-risk disease. BJU Int 110(6):821–827. doi:10.1111/j.1464-410X.2011. 10868.x Pettus JA, Weight CJ, Thompson CJ, Middleton RG, Stephenson RA (2004) Biochemical failure in men following radical retropubic prostatectomy: impact of surgical margin status and location. J Urol 172(1):129–132. doi:10.1097/01.ju.0000132160.68779.96 Spahn M, Briganti A, Capitanio U, Kneitz B, Gontero P, Karnes JR, Schubert M, Montorsi F, Scholz C-J, Bader P, van Poppel H, Joniau S (2012) Outcome predictors of radical prostatectomy followed by adjuvant androgen deprivation in patients with clinical high risk prostate cancer and pT3 surgical margin positive disease. J Urol 188(1):84–90 Savdie R, Horvath LG, Benito RP, Rasiah KK, Haynes AM, Chatfield M, Stricker PD, Turner JJ, Delprado W, Henshall SM, Sutherland RL, Kench JG (2012) High Gleason grade carcinoma at a positive surgical margin predicts biochemical failure after radical prostatectomy and may guide adjuvant radiotherapy. BJU Int 109(12):1794–1800. doi:10.1111/j.1464-410X.2011.10572.x Smith JA Jr, Chan RC, Chang SS, Herrell SD, Clark PE, Baumgartner R, Cookson MS (2007) A comparison of the incidence and location of positive surgical margins in robotic assisted laparoscopic radical prostatectomy and open retropubic radical prostatectomy. J Urol 178(6):2385–2389. doi:10.1016/j.juro. 2007.08.008; discussion 2389–2390 Hegarty NJ, Kaouk JH (2006) Radical prostatectomy: a comparison of open, laparoscopic and robot-assisted laparoscopic techniques. Can J Urol 13(Suppl 1):56–61 Swindle P, Eastham JA, Ohori M, Kattan MW, Wheeler T, Maru N, Slawin K, Scardino PT (2005) Do margins matter? The prognostic significance of positive surgical margins in radical prostatectomy specimens. J Urol 174(3):903–907. doi:10.1097/ 01.ju.0000169475.00949.78 Magheli A, Gonzalgo ML, Su LM, Guzzo TJ, Netto G, Humphreys EB, Han M, Partin AW, Pavlovich CP (2011) Impact of surgical technique (open vs laparoscopic vs robotic-assisted) on pathological and biochemical outcomes following radical prostatectomy: an analysis using propensity score matching. BJU Int 107(12):1956–1962. doi:10.1111/j.1464-410X.2010.09795.x Ahlering TE, Skarecky D, Lee D, Clayman RV (2003) Successful transfer of open surgical skills to a laparoscopic environment using a robotic interface: initial experience with laparoscopic radical prostatectomy. J Urol 170(5):1738–1741. doi:10.1097/01. ju.0000092881.24608.5e Patel VR, Tully AS, Holmes R, Lindsay J (2005) Robotic radical prostatectomy in the community setting—the learning curve and beyond: initial 200 cases. J Urol 174(1):269–272. doi:10.1097/01. ju.0000162082.12962.40 Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A (eds) (2010) AJCC cancer staging manual, 7th edn. Springer, New York, NY D’Amico AV, Whittington R, Malkowicz SB, Schultz D, Blank K, Broderick GA, Tomaszewski JE, Renshaw AA, Kaplan I, Beard CJ, Wein A (1998) Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer. J Am Med Assoc 280(11):969–974
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15. Udo K, Cronin AM, Carlino LJ, Savage CJ, Maschino AC, AlAhmadie HA, Gopalan A, Tickoo SK, Scardino PT, Eastham JA, Reuter VE, Fine SW (2013) Prognostic impact of subclassification of radical prostatectomy positive margins by linear extent and Gleason grade. J Urol 189(4):1302–1307 16. Budaus L, Isbarn H, Eichelberg C, Lughezzani G, Sun M, Perrotte P, Chun FK, Salomon G, Steuber T, Kollermann J, Sauter G, Ahyai SA, Zacharias M, Fisch M, Schlomm T, Haese A, Heinzer H, Huland H, Montorsi F, Graefen M, Karakiewicz PI (2010) Biochemical recurrence after radical prostatectomy: multiplicative interaction between surgical margin status and pathological stage. J Urol 184(4):1341–1346. doi:10.1016/j.juro.2010.06.018 17. Nyarangi-Dix JN, Radtke JP, Hadaschik B, Pahernik S, Hohenfellner M (2013) Impact of complete bladder neck preservation on urinary continence, quality of life and surgical margins after radical prostatectomy: a randomized, controlled, single blind trial. J Urol 189(3):891–898. doi:10.1016/j.juro.2012.09.082 18. Villers A (1994) Extracapsular tumor extension in prostatic cancer: pathways of spread and implications for radical prostatectomy. In: Stamey TA (ed) Monographs in urology, vol 15. Medical Directions, Mont-Verde, FL, pp 61–77 19. Ohori M, Abbas F, Wheeler TM, Kattan MW, Scardino PT, Lerner SP (1999) Pathological features and prognostic significance of prostate cancer in the apical section determined by whole mount histology. J Urol 161(2):500–504 20. Patel VR, Coelho RF, Rocco B, Orvieto M, Sivaraman A, Palmer KJ, Kameh D, Santoro L, Coughlin GD, Liss M, Jeong W, Malcolm J, Stern JM, Sharma S, Zorn KC, Shikanov S, Shalhav AL, Zagaja GP, Ahlering TE, Rha KH, Albala DM, Fabrizio MD, Lee DI, Chauhan S (2011) Positive surgical margins after robotic assisted radical prostatectomy: a multi-institutional study. J Urol 186(2):511–516. doi:10.1016/j.juro.2011.03.112 21. Schroeck FR, Sun L, Freedland SJ, Albala DM, Mouraviev V, Polascik TJ, Moul JW (2008) Comparison of prostate-specific antigen recurrence-free survival in a contemporary cohort of patients undergoing either radical retropubic or robot-assisted laparoscopic radical prostatectomy. BJU Int 102(1):28–32. doi:10.1111/j.1464-410X.2008.07607.x 22. Krambeck AE, DiMarco DS, Rangel LJ, Bergstralh EJ, Myers RP, Blute ML, Gettman MT (2009) Radical prostatectomy for prostatic adenocarcinoma: a matched comparison of open retropubic and robot-assisted techniques. BJU Int 103(4):448–453. doi:10.1111/j.1464-410X.2008.08012.x 23. Barocas DA, Salem S, Kordan Y, Herrell SD, Chang SS, Clark PE, Davis R, Baumgartner R, Phillips S, Cookson MS, Smith JA Jr (2010) Robotic assisted laparoscopic prostatectomy versus radical retropubic prostatectomy for clinically localized prostate cancer: comparison of short-term biochemical recurrence-free survival. J Urol 183(3):990–996. doi:10.1016/j.juro.2009.11.017 24. Drouin SJ, Vaessen C, Hupertan V, Comperat E, Misrai V, Haertig A, Bitker MO, Chartier-Kastler E, Richard F, Roupret M (2009) Comparison of mid-term carcinologic control obtained after open, laparoscopic, and robot-assisted radical prostatectomy for localized prostate cancer. World J Urol 27(5):599–605. doi:10.1007/s00345-009-0379-z 25. Liss MA, Lusch A, Morales B, Beheshti N, Skarecky D, Narula N, Osann K, Ahlering TE (2012) Robot-assisted radical prostatectomy: 5-year oncological and biochemical outcomes. J Urol 188(6):2205–2210. doi:10.1016/j.juro.2012.08.009 26. Boorjian SA, Thompson RH, Tollefson MK, Rangel LJ, Bergstralh EJ, Blute ML, Karnes RJ (2011) Long-term risk of clinical progression after biochemical recurrence following radical prostatectomy: the impact of time from surgery to recurrence. Eur Urol 59(6):893–899. doi:10.1016/j.eururo.2011.02.026 27. Freedland SJ, Humphreys EB, Mangold LA, Eisenberger M, Dorey FJ, Walsh PC, Partin AW (2005) Risk of prostate cancer-
World J Urol specific mortality following biochemical recurrence after radical prostatectomy. J Am Med Assoc 294(4):433–439. doi:10.1001/ jama.294.4.433 28. Roehl KA, Han M, Ramos CG, Antenor JA, Catalona WJ (2004) Cancer progression and survival rates following anatomical radical retropubic prostatectomy in 3,478 consecutive patients: longterm results. J Urol 172(3):910–914. doi:10.1097/01.ju. 0000134888.22332.bb
29. Song C, Ro JY, Lee MS, Hong SJ, Chung BH, Choi HY, Lee SE, Lee E, Kim CS, Ahn H (2006) Prostate cancer in Korean men exhibits poor differentiation and is adversely related to prognosis after radical prostatectomy. Urology 68(4):820–824. doi:10.1016/ j.urology.2006.04.029
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ORIGINAL ARTICLE
Impact of positive surgical margins and their locations after radical prostatectomy: comparison of biochemical recurrence according to risk stratification and surgical modality Min Soo Choo • Sung Yong Cho • Kyungtae Ko • Chang Wook Jeong Seung Bae Lee • Ja Hyeon Ku • Sung Kyu Hong • Seok-Soo Byun • Cheol Kwak • Hyeon Hoe Kim • Sang Eun Lee • Hyeon Jeong
•
Received: 8 September 2013 / Accepted: 12 December 2013 Ó Springer-Verlag Berlin Heidelberg 2013
Abstract Purpose We investigated the influence of positive surgical margins (PSMs) and their locations on biochemical recurrence (BCR) according to risk stratification and surgical modality. Methods A total of 1,874 post-radical-prostatectomy (RP) patients of pT2–T3a between 2000 and 2010 at three tertiary centers, and who did not receive neoadjuvant/adjuvant therapy, were included in this study. Patients were stratified according to BCR risk: low risk (PSA \10, pT2a-b, and pGS B6), intermediate risk (PSA 10–20 and/or pT2c and/or pGS 7), and high risk (PSA[20 or pT3a or pGS 8–10). The median follow-up was 43 months. Results PSMs were a significant predictor of BCR in both the intermediate- and high-risk-disease groups (P = .001, HR 2.1, 95 % CI 1.3–3.4; P \ .001, HR 2.8, 95 % CI 2.0–4.1). Positive apical margin was a significant risk factor for BCR in high-risk disease (P = .003, HR 2.0, 95 % CI 1.2–3.3), but not in intermediate-risk disease
(P = .06, HR 1.7, 95 % CI 0.9–3.1). Positive bladder neck margin was a significant risk factor for BCR in both intermediate- and high-risk disease (P \ .001, HR 5.4, 95 % CI 2.1–13.8; P = .001, HR 4.5, 95 % CI 1.8–11.4). In subgroup analyses, robotic RP provided comparable BCR-free survival regardless of risk stratification. Patients with PSMs showed similar BCR-free survival between open and robotic RP (log-rank, P = .897). Conclusions Post-RP PSMs were a significantly independent predictor of disease progression in high-risk disease as well as intermediate-risk disease. Both positive apical and bladder neck margins are also significant risk factors of BCR in high-risk disease. Patients with PSMs showed similar BCR-free survival between open and robotic surgery. Keywords Prostatic neoplasms Prostatectomy Neoplasm Residual Disease-free survival Robotics
Introduction M. S. Choo C. W. Jeong J. H. Ku C. Kwak H. H. Kim Department of Urology, Seoul National University Hospital, 28, Yongon-dong, Chongno-gu, Seoul 110-744, Korea S. Y. Cho S. B. Lee H. Jeong (&) Department of Urology, Seoul National University Boramae Hospital, Sindaebang 2-dong, 395, Dongjak-gu, Seoul 156-707, Korea e-mail: [email protected]; [email protected] K. Ko Department of Urology, Kangdong Sacred Heart Hospital, 150, Seongan-ro, Gangding-gu, Seoul 134-701, Korea S. K. Hong S.-S. Byun S. E. Lee Department of Urology, Seoul National University Bundang Hospital, 300 Gumi-dong, Bundang-gu, Seongnam-si, Seongnam 463-707, Korea
Positive surgical margin (PSM) implies incomplete tumor resection in surgical beds [1]. Its oncological significance to disease progression, however, remains controversial [2]. One recent study reported that PSM is not a significant risk factor for biochemical recurrence (BCR) in low- and highrisk diseases [3]. Also, controversial is the impact of PSM locations on BCR. The literature contains many conflicting reports. With respect specifically to the effect of positive apical margin (?AM) on BCR, the literature offers many contradictory reports [4]. The positive basal margin (?BM) is generally known to be a risk factor [5], though one investigator showed that it is not an independent predictor of BCR in low Gleason grade disease [6].
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Some reports have indicated that PSM rates might be related to surgical modalities and technique [7–9]. Another study recently showed that in high-stage disease, higher PSM rates are associated more with robot-assisted laparoscopic radical prostatectomy (RALP) rather than with retropubic radical prostatectomy (RRP), but that in low-stage disease, PSM rates do not differ [10]. However, there has been no study comparing the two modalities for BCR according to risk stratification. Moreover, there is no known comparative RRP/RALP study on how PSMs effect BCR. In the present study, we investigated the influence of PSMs and their locations on disease progression with pathological stage T2–T3a patients according to risk stratification and surgical modality.
Methods A total of 3,465 consecutive patients who had undergone RRP or RALP for clinically localized prostate cancer between January 2000 and December 2010 at three tertiary referral centers representing the same institution were enrolled in this study. Upon the approval of our institutional review board, we retrospectively collected clinical and pathological information on those patients. Follow-up data were gathered by means of chart review. All surgeons, who participated in this study, were experts and experienced enough to open (87–564 cases) or laparoscopic (over 150 cases) prostatectomy, and several reports showed that an experienced open surgeon successfully transferred open surgical skills to a robotic surgery in 8–25 cases [11, 12]. Therefore, with respect to each surgeon, the first 25 patients to undergo RALP were excluded owing to the learning curve. Additionally, a total of 252 patients who had undergone neoadjuvant therapy were excluded from the study. In order to isolate the effect of PSM locations on BCR, 469 patients with seminal vesicle invasion and/or positive lymph nodes, along with 254 patients who had undergone adjuvant therapy, were excluded. Also, 377 patients with\6 months of the followup and 24 patients with missing data were excluded. The patients with a detectable range of PSA over 0.2 ng/ml at the first follow-up visit were treated with adjuvant hormone therapy or radiotherapy, so those patients were excluded from the analyses. Thus, our final subjects numbered 1,874 patients were with disease of T2 and T3a pathological stages. The procedure according to which pathological specimens were processed was identical at each of the three hospitals. Prostatectomy specimens were processed according to the whole-mount technique and following the Stanford procedure, and were evaluated by 4 expert uro-
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pathologists. PSMs, defined as cancer cells reaching the inked surface, were categorized into four groups according to location: apex, bladder neck, posterolateral, and multifocal. Pathological staging was done using the seventh edition AJCC cancer staging system [13]. Follow-up visits were scheduled at 3-month intervals for 1 year, then semiannually for 1 year, and annually thereafter. Serum PSA level was checked at each follow-up visit. BCR was defined as a PSA [0.2 ng/ml or more on two consecutive measurements. Patients were stratified by BCR risk according to the modified D’Amico criteria as follows: low risk (PSA \10, pT2a–b stage, and GS B6), intermediate risk (PSA 10–20 and/or pT2c stage and/or GS 7), and high risk (PSA[20 or pT3a stage or GS 8–10) [14]. Robotic surgery at our institution begun in July 2008. In a subgroup analysis comparing robotic with open surgery, patients who had undergone RRP since that time were included. The choice of surgical approach accorded with patient preference after discussion of the risks, benefits, and alternatives with the attending surgeon. RRP was performed using the modified Walsh anatomical modality, and RALP was performed, using the transperitoneal antegrade approach and the da Vinci Robot System. We performed pelvic lymph node dissection (PLND) in most of the high-risk patients in D’Amico criteria, and the necessity of PLND in intermediate-risk patients was determined with the discretion of attending surgeon. The boundary of PLND included obturator, and external and internal iliac lymph nodes in most patients. The nerve-sparing procedure was performed if clinically indicated by patient age, preoperative erectile function, and oncological parameters. Comparisons between subject groups were conducted using the Student’s t test or Pearson v2 test, and the respective clinicopathological variables were analyzed using Pearson v2 tests. To determine the effect of risk group as well as surgical margin status and its location on BCR risk, Kaplan–Meier curves were generated, and differences were compared by log-rank test and Cox proportional hazard regression analysis. Significant variables on univariate analysis were included in the multivariate model. A two-sided P value \.05 was considered significant. Statistical results were calculated using the SPSS software package (ver. 14.0, SPSS Inc., Chicago, IL, USA).
Results The clinical and pathological characteristics of the 1,874 patients are provided in Table 1. Overall, 462 (24.7 %) patients were reported to have PSMs. The PSM rate rose from 8.9 % in low-, to 20.3 % in intermediate-, and to 32.6 % in high-risk disease (P \ .001). With a median follow-up of 43 months, 245 (13.1 %) patients experienced
World J Urol Table 1 Clinicopathological characteristics according to SMs status and their locations (%) Characteristics
Overall
SMs status Negative
P value Positive
Apex
N
1,874
1,411 (75.3)
463 (24.7)
Age (years)
65.3 ± 6.9
65.1 ± 7.0
65.9 ± 6.5
PSA (ml/ng)
8.5 ± 6.9
8.0 ± 6.2
9.8 ± 8.6
\10
1,410 (75.2)
1,091 (77.3)
317 (68.5)
10–20
365 (19.5)
258 (18.2)
108 (23.3)
[20
99 (5.3)
62 (4.4)
38 (8.2)
Biopsy GS 6 or less
SMs locations
P value BN
190 (10.1)
32 (1.7)
65.6 ± 6.2
66.5 ± 5.8
.458
\.001
9.5 ± 8.3
7.7 ± 5.0
.264
\.001
140 (73.7)
23 (71.9)
.459
35 (18.4)
8 (25.0)
15 (7.8)
1 (3.1)
105 (55.3)
18 (56.2)
.027
\.001
.790
1,145 (61.1)
897 (63.5)
248 (53.5)
7
528 (28.2)
381 (27.0)
147 (31.7)
56 (29.4)
10 (31.2)
8–10
201 (10.7)
133 (9.4)
68 (14.6)
29 (15.3)
4 (12.5)
T1
1,346 (71.8)
1,031 (73.0)
315 (68.0)
130 (68.4)
24 (75.0)
T2
528 (28.2)
380 (26.9)
148 (31.9)
60 (31.6)
8 (25.0)
191 (10.2)
174 (12.4)
17 (3.7)
7 (3.7)
2 (6.3)
Intermediate
819 (43.7)
652 (46.2)
165 (35.7)
85 (44.7)
14 (43.8)
High
864 (46.1)
585 (41.4)
281 (60.6)
98 (51.5)
16 (50.0)
Prostate (vol, ml)
40.9 ± 17.6
42.0 ± 18.0
37.4 ± 15.8
37.1 ± 4.6
35.9 ± 7.9
Clinical stage
.045
\.001
Risk group Low
.457
Op. methods
\.001
.803
.450
.537 .265
RRP
1,277 (68.1)
968 (68.6)
309 (66.7)
147 (77.4)
RALP
597 (31.9)
443 (31.4)
154 (33.3)
43 (22.6)
21 (65.6) 11 (34.3)
PLND NVB saving
622 (33.2) 769 (41.0)
447 (31.6) 577 (40.8)
175 (37.7) 192 (41.4)
.008 .596
54 (28.7) 72 (38.3)
11 (34.3) 13 (40.7)
.277 .673
Tumor (vol, ml)
4.2 ± 13.5
3.7 ± 15.2
5.5 ± 6.4
.020
5.1 ± 4.6
5.5 ± 4.6
.661
pT2a, b
443 (23.6)
389 (27.5)
54 (11.6)
25 (13.2)
5 (15.6)
pT2c
661 (35.2)
509 (36.1)
152 (32.8)
79 (41.5)
13 (40.6)
pT3a
770 (41.1)
513 (36.4)
257 (55.5)
86 (45.3)
14 (43.8)
\.001
Pathological stage
.731
\.001
Pathological GS
.476
6 or less
734 (39.1)
609 (43.2)
125 (27.0)
46 (24.2)
7
1,047 (55.8)
738 (52.3)
309 (66.7)
130 (68.4)
19 (59.4)
8–10
93 (5.0)
64 (4.5)
29 (6.3)
14 (7.4)
2 (6.2)
BCR. The BCR rates were 6.8 % in low-, 11.6 % in intermediate-, and 15.9 % in high-risk disease. Figure 1 shows the effect of surgical margin status on BCR risk according to the disease group. Among all of the patients, PSM was an independent predictor of BCR. Pelvic lymph node dissection or neurovascular bundle sparing was not associated with BCR. Patients with low-risk disease had similar risks of BCR regardless of surgical margin status and locations. By contrast, in patients with both intermediate- and high-risk disease, PSM was a significant predictor of BCR on univariate analysis (P = .001 and P \ .001). On multivariate analysis, including preoperative PSA level, pathological stage, and Gleason score, PSM was an independent predictive factor of BCR in patients with
11 (34.4)
both intermediate- and high-risk disease (HR 2.1 and 2.8) (Table 2). Figure 1 also shows the impact of PSM location on BCR according to risk group. Both ?AM and ?BM were significant risk factors for BCR among all of the patients. On univariate analyses, ?AM and ?BM were significant predictors of BCR in both the intermediate- and high-riskdisease groups. However, on multivariate analyses, the impact of ?AM did not attain significance in the intermediate-risk group (P = .06, HR 1.7, 95 % CI 0.9–3.1). In the high-risk group, by contrast, ?AM was a significant risk factor for BCR (HR 2.0). ?BM was a significant independent predictor of BCR in both the intermediate- and high-risk groups (HR 5.4 and HR 4.5) (Table 2).
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Fig. 1 BCR-free survival stratified by margin status and its sites according to risk-disease groups. a Overall. b Low risk. c Intermediate risk. d High risk
In a subgroup analysis comparing the surgical modalities, 352 and 559 patients received RRP or RALP since July 2008, respectively. The median follow-up was 35 months in the RRP group and 39 months in the RALP group. Patients undergoing RALP had a significantly lower age and prostate volume, but similar PSA, pathological stage, and pathological Gleason scores. There was no significant difference in the PSM rates between the RRP and RALP groups (23.7 vs. 25.2 %). On survival analysis, the overall BCR-free survival rates were similar in the two treatment groups (Fig. 2a). Neither were there significant
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differences for risk group stratification (Fig. 2). On multivariate analysis, the surgical modality was not a significant predictor of BCR (P = .718, HR 0.9, 95 % CI 0.5–1.5) (Table 2). The impact of PSMs on BCR was similar in the RRP and RALP groups (Fig. 3).
Discussion The present results indicate that PSMs in RP specimens without seminal vesicle or lymph node involvement are
World J Urol Table 2 Multiple Cox proportional hazards models for BCR predictors Risk group
Variables
Overall
SM
PSA GS pStage
Low
Intermediate
High
Stratification
P
HR
95 % CIs
-SM versus ?SM
\.001
2.6
1.9–3.4
-SM versus ?AM
\.001
1.9
1.3–2.7
-SM versus ?BM
\.001
5.0
2.7–9.4
\10 versus 10–20
\.001
1.7
1.2–2.3
\10 versus C20
\.001
2.2
1.4–3.5
6 versus 7
.002
1.7
1.2–2.4
6 versus 8, 9, 10
\.001
4.5
2.8–7.2
2a, b versus 2c
.20
1.2
0.8–1.8
2a, b versus 3a
.54
1.1
0.7–1.6
Op.
RRP versus RALP
.718
0.9
0.5–1.5
SM PSA
-SM versus ?SM -
.07 –
3.2 –
0.8–11.9 –
GS
-
–
–
–
pStage
-
–
–
–
SM
-SM versus ?SM
.001
2.1
1.3–3.4
-SM versus ?AM
.06
1.7
0.9–3.1
-SM versus ?BM
\.001
5.4
2.1–13.8
PSA
\10 versus 10–20
.04
1.5
1.0–2.4
GS
6 versus 7
.08
1.5
0.9–2.5
pStage
2a, b versus 2c
.02
2.1
1.3–3.3
SM
-SM versus ?SM
\.001
2.8
2.0–4.1
-SM versus ?AM
.003
2.0
1.2–3.3
-SM versus ?BM
.001
4.5
1.8–11.4
\10 versus 10–20
.007
1.7
1.1–2.7
\10 versus C20
.001
2.2
1.4–3.6
PSA GS pStage
6 versus 7
.001
3.1
1.5–6.3
6 versus 8, 9, 10
\0.001
8.1
3.7–17.6
2a, b versus 2c
.95
0.9
0.4–2.2
2a, b versus 3a
.94
0.9
0.4–2.0
Low-risk group: PSA \ 10 and GS B 6 and pStage 2a or 2b, intermediate-risk group: PSA 10–20 or GS 7 or pStage 2c, high-risk group PSA C 20 or GS C 8 or pStage 3a
significant predictive factors for disease progression in both intermediate- and high-risk disease. Furthermore, both ?AM and ?BM are significant independent predictors of BCR in high-risk disease. Subgroup analyses showed similar BCR-free survival for RRP and RALP regardless of risk stratification. Patients with PSMs, moreover, showed similar BCR-free survival rates between RRP and RALP. To our knowledge, this is the first study comparing BCR rates among a contemporary series of Asian patients undergoing either RRP or RALP. In this study, PSM patients in intermediate- and highrisk-disease groups had higher rates of BCR than those who were margin-negative. However, PSM in the low-riskdisease group was not associated with disease progression. Corcoran et al. [3] insisted that in low- or high-risk disease, PSMs are not associated with BCR, because they are only a reflection either of indolent low-risk nature or inherent
aggressiveness. However, in our data on Korean men, PSMs also were an independent predictor of BCR in the high-risk-disease group. Additionally PSMs had a more adverse effect in the high-risk-disease group than in the intermediate-risk-disease group (HR 2.8 vs. 2.1). Most recently studies reported that PSMs in high-grade and highstage disease are more relevant to recurrence risk [15, 16]. In our results, we observed that about 75 % of patients with extremely high-risk-disease features such as GS C8, PSA C20, and extracapsular extension enjoyed BCR-free survival for over 8 years after undergoing complete resection. Thus, all surgeons should attempt to achieve negative surgical margins regardless of disease status and should also actively consider adjuvant therapy for high-risk-disease patients with PSMs. After adjusting for differences in clinical and pathological features, the presence of ?BM was significantly
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Fig. 2 BCR-free survival stratified by surgical modalities according to risk-disease groups. a Overall. b Low risk. c Intermediate risk. d High risk
associated with a shorter time to recurrence in intermediate- and high-risk disease. Spahn et al. [5] suggested that patients with PSMs at the bladder neck can be considered to have the poorest prognosis (HR 4.4). Nyarangi-Dix et al. [17] also noted that ?BM is usually associated with higherstage tumor. In our data, the ?BM patients accounted for 93.8 % of the combined membership in the intermediateand high-risk-disease groups. Villers postulated that the base of the prostate wound offers a preferred pathway for cancer dissemination between intraprostatic and periprostatic neural tissue close to the superior neurovascular
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bundle [18]. Emphatically, ?BM indicates that aggressive cancer remains on the pathway to systemic dissemination. In the present study, patients with ?AM were 1.9 times more likely to have a shorter time to recurrence (P \ .001) overall. In high-risk disease, the ?AM also was associated with the time to recurrence, but not statistically in intermediate-risk disease (P = .06). Although several theories have been proposed to explain how ?AM can be less likely to result in BCR than other locations, Ohori et al. [19] reported that apical disease correlates with higher tumor volume, a higher incidence of extracapsular extension, and
World J Urol
Fig. 3 BCR-free survival stratified by surgical modalities and margin status
higher tumor grade. Pettus et al. [4] implied that ?AM is important in high-stage disease, but less important in lowstage disease. In Korean men with a relatively small prostate volume, ?AM can be a true positive rather than false one. Patel et al. [20] described that significantly greater incidence of PSMs in the smaller than in the larger prostate weight group. Actually, our data showed that patients who experienced BCR with ?AM had a smaller prostate volume than those who did not (34 vs. 37 g), but not to a statistically meaningful extent (P = .228). Thus, ?AM also should be kept in mind as a risk factor when considering further management in Korean men. We found that surgical modality was not a risk factor for disease progression. Recently, Savdie et al. [6] found that the Gleason grade of a PSM identified patients at increased risk of BCR. Similarly, we assumed that the pathological features of the remaining tumors at the PSM after surgery might be different between the two surgical modalities, because of the different surgical technique. We also investigated the influence of PSMs on the BCR according to risk stratification, because more aggressive tumors could be remained at the PSM in high-risk patients group. Thus, the similar PSM rate would not mean the similar BCR rate, and the prognostic value of PSM may be different in RALP compared to RRP. Several recent studies have reported similar BCR rates for RRP and RALP groups, but those were limited by the short follow-up or small patient groups [21–24]. In our contemporary, relative large- and mid-term studies, there was no significant difference in the BCR risk between the RALP and
RRP groups after adjustment for differences in clinical and pathological features. Although there are a few previous reports that surgical modality affects PSM rates [7, 10], the impact of PSMs on BCR likelihood was similar between the two present-study groups. To our knowledge, this is the first investigation to compare BCR between RRP and RALP according to PSMs. In the results, post-RP PSMs were associated with higher BCR rates and shorter times to progression, regardless of surgical modality. A limitation of this investigation is the relatively short follow-up periods for RALP patients. Nonetheless, considering that the most recent relevant large-scale studies reported a median post-RP time to recurrence of 24–37 months [25–28], our mean 36.3-month (median 39 months) follow-up data are perhaps reasonable. And this study is inherent in any retrospective, nonrandomized analysis. The difference in costs between the two modalities is great, so randomized controlled study cannot be performed in Korea. Nevertheless, we were careful to apply a number of strict inclusion and exclusion criteria. Thus, there was minimal bias in the subjects. Another limitation is the lack of a central pathological review. However, as the three hospitals involved in the present investigation are affiliated with the same institution, all of the participating pathologists used exactly the same pathological evaluation methods. Also, all of the specimenexamining pathologists were urology specialists. High margin rate in organ-confined disease of this cohort is one of the drawbacks of the present study. The pelvis shape of Korean men was narrow and deep, and it makes surgery difficult. The ethnic differences in the clinicopathological characteristics of prostate cancer are thought to be affected [29]. Also, our institutions are tertiary referral centers, and it might not reflect epidemiological trends.
Conclusions In conclusion, this study demonstrates that post-RP PSMs are significant independent predictors of disease progression in both high-risk and intermediate-risk disease. Both ?AM and ?BM, furthermore, also are significant BCR risk factors in high-risk disease. In the results of subgroup analyses, RALP could provide comparable BCR-free survival regardless of risk stratification. Conflict of interest
None.
References 1. Blute ML, Bostwick DG, Bergstralh EJ, Slezak JM, Martin SK, Amling CL, Zincke H (1997) Anatomic site-specific positive margins in organ-confined prostate cancer and its impact on
123
World J Urol
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
outcome after radical prostatectomy. Urology 50(5):733–739. doi:10.1016/S0090-4295(97)00450-0 Boorjian SA, Tollefson MK, Thompson RH, Rangel LJ, Bergstralh EJ, Karnes RJ (2012) Natural history of biochemical recurrence after radical prostatectomy with adjuvant radiation therapy. J Urol 188(5):1761–1766 Corcoran NM, Hovens CM, Metcalfe C, Hong MK, Pedersen J, Casey RG, Peters J, Harewood L, Goldenberg SL, Costello AJ, Gleave ME (2012) Positive surgical margins are a risk factor for significant biochemical recurrence only in intermediate-risk disease. BJU Int 110(6):821–827. doi:10.1111/j.1464-410X.2011. 10868.x Pettus JA, Weight CJ, Thompson CJ, Middleton RG, Stephenson RA (2004) Biochemical failure in men following radical retropubic prostatectomy: impact of surgical margin status and location. J Urol 172(1):129–132. doi:10.1097/01.ju.0000132160.68779.96 Spahn M, Briganti A, Capitanio U, Kneitz B, Gontero P, Karnes JR, Schubert M, Montorsi F, Scholz C-J, Bader P, van Poppel H, Joniau S (2012) Outcome predictors of radical prostatectomy followed by adjuvant androgen deprivation in patients with clinical high risk prostate cancer and pT3 surgical margin positive disease. J Urol 188(1):84–90 Savdie R, Horvath LG, Benito RP, Rasiah KK, Haynes AM, Chatfield M, Stricker PD, Turner JJ, Delprado W, Henshall SM, Sutherland RL, Kench JG (2012) High Gleason grade carcinoma at a positive surgical margin predicts biochemical failure after radical prostatectomy and may guide adjuvant radiotherapy. BJU Int 109(12):1794–1800. doi:10.1111/j.1464-410X.2011.10572.x Smith JA Jr, Chan RC, Chang SS, Herrell SD, Clark PE, Baumgartner R, Cookson MS (2007) A comparison of the incidence and location of positive surgical margins in robotic assisted laparoscopic radical prostatectomy and open retropubic radical prostatectomy. J Urol 178(6):2385–2389. doi:10.1016/j.juro. 2007.08.008; discussion 2389–2390 Hegarty NJ, Kaouk JH (2006) Radical prostatectomy: a comparison of open, laparoscopic and robot-assisted laparoscopic techniques. Can J Urol 13(Suppl 1):56–61 Swindle P, Eastham JA, Ohori M, Kattan MW, Wheeler T, Maru N, Slawin K, Scardino PT (2005) Do margins matter? The prognostic significance of positive surgical margins in radical prostatectomy specimens. J Urol 174(3):903–907. doi:10.1097/ 01.ju.0000169475.00949.78 Magheli A, Gonzalgo ML, Su LM, Guzzo TJ, Netto G, Humphreys EB, Han M, Partin AW, Pavlovich CP (2011) Impact of surgical technique (open vs laparoscopic vs robotic-assisted) on pathological and biochemical outcomes following radical prostatectomy: an analysis using propensity score matching. BJU Int 107(12):1956–1962. doi:10.1111/j.1464-410X.2010.09795.x Ahlering TE, Skarecky D, Lee D, Clayman RV (2003) Successful transfer of open surgical skills to a laparoscopic environment using a robotic interface: initial experience with laparoscopic radical prostatectomy. J Urol 170(5):1738–1741. doi:10.1097/01. ju.0000092881.24608.5e Patel VR, Tully AS, Holmes R, Lindsay J (2005) Robotic radical prostatectomy in the community setting—the learning curve and beyond: initial 200 cases. J Urol 174(1):269–272. doi:10.1097/01. ju.0000162082.12962.40 Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A (eds) (2010) AJCC cancer staging manual, 7th edn. Springer, New York, NY D’Amico AV, Whittington R, Malkowicz SB, Schultz D, Blank K, Broderick GA, Tomaszewski JE, Renshaw AA, Kaplan I, Beard CJ, Wein A (1998) Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer. J Am Med Assoc 280(11):969–974
123
15. Udo K, Cronin AM, Carlino LJ, Savage CJ, Maschino AC, AlAhmadie HA, Gopalan A, Tickoo SK, Scardino PT, Eastham JA, Reuter VE, Fine SW (2013) Prognostic impact of subclassification of radical prostatectomy positive margins by linear extent and Gleason grade. J Urol 189(4):1302–1307 16. Budaus L, Isbarn H, Eichelberg C, Lughezzani G, Sun M, Perrotte P, Chun FK, Salomon G, Steuber T, Kollermann J, Sauter G, Ahyai SA, Zacharias M, Fisch M, Schlomm T, Haese A, Heinzer H, Huland H, Montorsi F, Graefen M, Karakiewicz PI (2010) Biochemical recurrence after radical prostatectomy: multiplicative interaction between surgical margin status and pathological stage. J Urol 184(4):1341–1346. doi:10.1016/j.juro.2010.06.018 17. Nyarangi-Dix JN, Radtke JP, Hadaschik B, Pahernik S, Hohenfellner M (2013) Impact of complete bladder neck preservation on urinary continence, quality of life and surgical margins after radical prostatectomy: a randomized, controlled, single blind trial. J Urol 189(3):891–898. doi:10.1016/j.juro.2012.09.082 18. Villers A (1994) Extracapsular tumor extension in prostatic cancer: pathways of spread and implications for radical prostatectomy. In: Stamey TA (ed) Monographs in urology, vol 15. Medical Directions, Mont-Verde, FL, pp 61–77 19. Ohori M, Abbas F, Wheeler TM, Kattan MW, Scardino PT, Lerner SP (1999) Pathological features and prognostic significance of prostate cancer in the apical section determined by whole mount histology. J Urol 161(2):500–504 20. Patel VR, Coelho RF, Rocco B, Orvieto M, Sivaraman A, Palmer KJ, Kameh D, Santoro L, Coughlin GD, Liss M, Jeong W, Malcolm J, Stern JM, Sharma S, Zorn KC, Shikanov S, Shalhav AL, Zagaja GP, Ahlering TE, Rha KH, Albala DM, Fabrizio MD, Lee DI, Chauhan S (2011) Positive surgical margins after robotic assisted radical prostatectomy: a multi-institutional study. J Urol 186(2):511–516. doi:10.1016/j.juro.2011.03.112 21. Schroeck FR, Sun L, Freedland SJ, Albala DM, Mouraviev V, Polascik TJ, Moul JW (2008) Comparison of prostate-specific antigen recurrence-free survival in a contemporary cohort of patients undergoing either radical retropubic or robot-assisted laparoscopic radical prostatectomy. BJU Int 102(1):28–32. doi:10.1111/j.1464-410X.2008.07607.x 22. Krambeck AE, DiMarco DS, Rangel LJ, Bergstralh EJ, Myers RP, Blute ML, Gettman MT (2009) Radical prostatectomy for prostatic adenocarcinoma: a matched comparison of open retropubic and robot-assisted techniques. BJU Int 103(4):448–453. doi:10.1111/j.1464-410X.2008.08012.x 23. Barocas DA, Salem S, Kordan Y, Herrell SD, Chang SS, Clark PE, Davis R, Baumgartner R, Phillips S, Cookson MS, Smith JA Jr (2010) Robotic assisted laparoscopic prostatectomy versus radical retropubic prostatectomy for clinically localized prostate cancer: comparison of short-term biochemical recurrence-free survival. J Urol 183(3):990–996. doi:10.1016/j.juro.2009.11.017 24. Drouin SJ, Vaessen C, Hupertan V, Comperat E, Misrai V, Haertig A, Bitker MO, Chartier-Kastler E, Richard F, Roupret M (2009) Comparison of mid-term carcinologic control obtained after open, laparoscopic, and robot-assisted radical prostatectomy for localized prostate cancer. World J Urol 27(5):599–605. doi:10.1007/s00345-009-0379-z 25. Liss MA, Lusch A, Morales B, Beheshti N, Skarecky D, Narula N, Osann K, Ahlering TE (2012) Robot-assisted radical prostatectomy: 5-year oncological and biochemical outcomes. J Urol 188(6):2205–2210. doi:10.1016/j.juro.2012.08.009 26. Boorjian SA, Thompson RH, Tollefson MK, Rangel LJ, Bergstralh EJ, Blute ML, Karnes RJ (2011) Long-term risk of clinical progression after biochemical recurrence following radical prostatectomy: the impact of time from surgery to recurrence. Eur Urol 59(6):893–899. doi:10.1016/j.eururo.2011.02.026 27. Freedland SJ, Humphreys EB, Mangold LA, Eisenberger M, Dorey FJ, Walsh PC, Partin AW (2005) Risk of prostate cancer-
World J Urol specific mortality following biochemical recurrence after radical prostatectomy. J Am Med Assoc 294(4):433–439. doi:10.1001/ jama.294.4.433 28. Roehl KA, Han M, Ramos CG, Antenor JA, Catalona WJ (2004) Cancer progression and survival rates following anatomical radical retropubic prostatectomy in 3,478 consecutive patients: longterm results. J Urol 172(3):910–914. doi:10.1097/01.ju. 0000134888.22332.bb
29. Song C, Ro JY, Lee MS, Hong SJ, Chung BH, Choi HY, Lee SE, Lee E, Kim CS, Ahn H (2006) Prostate cancer in Korean men exhibits poor differentiation and is adversely related to prognosis after radical prostatectomy. Urology 68(4):820–824. doi:10.1016/ j.urology.2006.04.029
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